Abstract

Lemierre’s syndrome (postanginal septicaemia/human necrobacillosis) was first defined and described in 1936 by Lemierre, a French Physician and Professor in Microbiology, although the first case report of human necrobacillosis was published in 1900 by Courmont and Cade [1,2]. Lemierre’s syndrome has come to be known as the “forgotten” disease, as very few cases have been reported since the introduction and widespread use of antibiotics [3,4]. In the preantibiotic era, Lemierre’s Syndrome was associated with a mortality rate of approximately 90% [1]. Currently, the associated mortality rate is estimated to range from 5% to 10% [5-7]. Since 1974, less than 100 cases have been reported [8,9]. This can be explained by the fact that more throat infections received early treatment with the widespread use of antibiotics, leading to the decrease in the incidence of Lemierre’s disease. The syndrome is characterised by a recent history of oropharyngitis with persistent fevers, followed by septic thrombophlebitis of the internal jugular vein and dissemination of the infection to multiple sites distant to the pharynx [10]. Fusobacterium species are responsible in most cases. It affects previously healthy adolescents and young adults.

Introduction

Lemierre’s syndrome (postanginal septicaemia/human
necrobacillosis) was first defined and described in 1936 by Lemierre,
a French Physician and Professor in Microbiology, although the
first case report of human necrobacillosis was published in 1900 by
Courmont and Cade [1,2]. Lemierre’s syndrome has come to be known
as the “forgotten” disease, as very few cases have been reported since
the introduction and widespread use of antibiotics [3,4]. In the preantibiotic
era, Lemierre’s Syndrome was associated with a mortality
rate of approximately 90% [1]. Currently, the associated mortality
rate is estimated to range from 5% to 10% [5-7]. Since 1974, less
than 100 cases have been reported [8,9]. This can be explained by
the fact that more throat infections received early treatment with the
widespread use of antibiotics, leading to the decrease in the incidence
of Lemierre’s disease. The syndrome is characterised by a recent
history of oropharyngitis with persistent fevers, followed by septic
thrombophlebitis of the internal jugular vein and dissemination of the
infection to multiple sites distant to the pharynx [10]. Fusobacterium species are responsible in most cases. It affects previously healthy
adolescents and young adults.

Case Report

A previously healthy 44 year old female was seen in the Emergency
Department with a 3 day history of progressively worsening sore throat
predominantly to the left with associated fevers and vomiting. She
deteriorated rapidly over the last 24 hours before presenting to the
hospital, with significant odynophagia, vomiting and dehydration. On
examination, she was febrile (39.8°C), hypotensive (92/50 mm of Hg)
and tachycardic (142 beats per minute). Throat examination revealed
an erythematous left tonsil pushed medially. On examination of the
neck, there was associated tender cervical lymphadenopathy. Lung
fields were clear on auscultation. Abdominal examination did not
reveal any organomegaly or tenderness. Investigations at the time
of admission showed White Cell Count (WCC) 29.0×109 L with a
platelet count of 37/mm3, International Normalised Ratio (INR) of
2.2, C-Reactive Protein (CRP) of 211 along with deranged liver and
kidney function tests. Initial chest radiography revealed normal lung
fields. She required acute resuscitation and intensive care admission.
She underwent a Computerised Tomography (CT) of the neck with
contrast which revealed a collection in the left peritonsillar region
(Figure 1). Drainage of the peritonsilllar abscess was deferred due to
coagulopathy. She rapidly deteriorated despite intravenous antibiotics
and developed coagulopathy, acute renal failure, encephalopathy,
respiratory failure and bilateral pleural effusions (Figure 2). She required
inotropic support, mechanical ventilation and dialysis. Intravenous
antibiotic therapy included Lincomycin and Meropenem with blood
cultures pending. Blood cultures grew Fusobacterium necrophorum (subspecies not identified), sensitive to Penicillin and Metronidazole.
Antibiotics were changed accordingly to Piperacillin-Tazobactam and
Metronidazole. A diagnosis of Lemierre’s syndrome was made. The left
peritonsillar abscess was drained on the sixth day of admission after the
reversal of coagulopathy with fresh frozen plasma. An improvement
in her condition was noted and she was successfully extubated on the
ninth day after admission. She was discharged home on thirteenth day on a week’s course of Amoxycillin-Clavulanic acid. She has remained
asymptomatic and well since discharge. She was followed up in Ear,
Nose and Throat (ENT) outpatient clinics 2 months later but did not
require any further treatment.

Figure 1: Computerised Tomography of the neck (Axial view) of a 44 year
old female showing peripherally enhancing peritonsillar collection (arrow) with
mass effect on the adjacent parapharyngeal space. Endotracheal tube in situ.

Figure 2: Chest Radiograph of 44 year old female showing bilateral pleural
effusions with associated right lower lobe collapse / consolidation and patchy
opacities in the left mid-zone.

Discussion

Fusobacterium necrophorum is a gram-negative anaerobe
responsible for Lemierre`s syndrome in 90% cases and has been
detected in 10% of all acute sore throats and 21% of all recurring sore
throats with the remainder caused by group A streptococci or viruses
[11,12]. F. necrophorum is conventionally thought to be a part of the
normal flora of the pharynx, gastrointestinal tract, and female genital
tract but there is no convincing evidence of the same [12]. It can invade
as a primary pathogen due to its ability to produce lipopolysaccharide
endotoxin, leukocidin, and haemolysin [13]. It has been shown to
release bradykinin and activate the intrinsic pathway of coagulation by
activating the contact system through direct binding of high molecular
weight kininogen and factor XI, respectively [14]. Bacteroides,
Streptococcus, Peptostreptococcus and Eikenella are other organisms
that have been isolated from the patients with Lemierre’s syndrome
[10,15]. Palatine tonsils and peritonsillar tissue are the prime sources
of infection. The infection may spread to involve the parapharyngeal
space leading to secondary thrombophlebitis of the tonsillar veins, which can propagate thrombus formation to the internal jugular vein
[6,9,16].

The patients present with a history of a recent sore throat within
the last week with high grade temperatures ranging between 39-41
degrees often followed by a rigor [1,17,18]. At the time of presentation,
the throat may vary from a normal looking oropharynx to a severe
exudative tonsillitis or peritonsillitis [9,12,19]. Neck pain, stiffness and
cervical lymphadenopathy are often present due to the development
of thrombus in the Internal Jugular Vein (IJV). Sometimes, this may
have concomitant trismus, otalgia and dysphagia [20]. Local septic
complications include peritonsillar abscess, internal jugular vein
thrombosis, parapharyngeal abscess and paratracheal abscess [21,22].

Evidence of internal jugular vein thrombosis is radiologically
evident either by ultrasonography or CT, in approximately 30-70%
of the patients [6,13]. The thrombus releases septic emboli leading to
metastatic infections. The most commonly involved organs are the
lungs. There may be associated pleural effusion, empyema, bilateral
pulmonary infiltrates or multiple cavitating lesions [23-26]. A rather
rapid progression of lung lesions and pleural effusion is noted in these
patients despite antibiotic therapy. Pneumatocoeles, pneumothorax
and adult respiratory distress syndrome are uncommon complications
[26-29]. Bearing in mind the aggressive nature of disease progression
and severity of septicaemic illness, acute respiratory distress syndrome is
noted in only a very small subset of those diagnosed, with less than 10%
requiring mechanical ventilation [30]. Septic arthritis, osteomyelitis,
pericarditis, hepatic abscesses are other metastatic manifestations.
The spleen, skin, kidneys, brain and soft tissue may rarely be involved
[24,31,32]. There may be associated splenomegaly, hepatomegaly and
jaundice. Liver function tests are deranged in 49% of the patients with
hyperbilirubinaemia [33]. Blood picture reveals leucocytosis in most
cases with thrombocytopenia in some. Renal involvement may result
in renal insufficiency with haematuria, pyuria, proteinuria and uraemia
[5,34-36]. Activation of the intrinsic pathway of coagulation can lead to
coagulopathy and disseminated intravascular coagulation [14].

A high degree of suspicion is required to aid in the diagnosis.
The diagnosis is usually not reached until the blood culture results
are available which may take at least 48 hours and sometimes up to
7 days. Radiological studies especially contrast enhanced CT can
confirm clinical suspicions. The images reveal distended veins with enhancement of the vessel walls, intramural filling defects and adjacent
soft tissue swelling [37]. Local complications like peritonsillar abscess
are also visualised on CT. Doppler ultrasound, Magnetic Resonance
Angiography (MRA), gallium scan and radionuclide venography may
sometimes be required. CT and plain chest radiographs are used to look
for lung involvement. An ultrasound examination of the abdomen may
be undertaken when hepatic or splenic abscesses are suspected [37-41].

Intravenous antibiotics are the mainstay of treatment. Slow
improvement in the clinical picture despite appropriate antibiotics
therapy may be noted. Majority of the patients treated with antibiotics
in a timely manner show a favourable outcome. Poorer outcomes are
seen with delayed treatment. Fusobacterium necrophorum is found to
be sensitive to beta-lactam antibiotics, metronidazole, clindamycin and
third generation cephalosporins [13,34,42]. Due to a high probability
of a co-infection by another bacterium, monotherapy is not advised
for the treatment of Lemierre’s syndrome. Patients should be treated
with penicillin combined with a beta-lactamase inhibitor such as
clavulanic acid or with metronidazole for a total of 6 weeks [5,6,15,43].
Clindamycin can be given as a single agent. Surgical excision and
ligation of the IJV is rarely required and reserved for patients with
ongoing sepsis and septic embolization resulting in repetitive embolic
manifestations [6,9,15,44].

The role of anticoagulation in the treatment of Lemierre’s syndrome
remains controversial. Heparin use in these patients may shorten
the course of the disease and the need of surgical intervention [45].
Patients may be anticoagulated for possible early clot dissolution but
should be easily reversible if the need for surgical intervention arises. It
needs to be kept in mind that these patients are usually coagulopathic
and hence the presence of thrombophilia should be used as a guide to
the need of anticoagulation. Sigmoid sinus thrombosis is an indication
that warrants anticoagulation [19,25,46,47]. The recommended
anticoagulation regime, if indicated should include one week of
intravenous heparin followed by 3 months of oral warfarin [19,47].
Hyperbaric oxygen has also been used with some evidence to support a
favourable and rapid improvement in patients’ condition [48].

Conclusion

Pharyngitis with associated clinical picture of IJV thrombophlebitis,
sepsis or septic emboli should raise the possibility of Lemierre’s
syndrome in the treating clinician’s mind leading to appropriate
treatment and investigations. Early recognition of the syndrome is vital
for prompt and appropriate therapy as blood cultures may take several
days. Bearing in mind, the clinical suspicion of Lemierre’s syndrome,
patients presenting with pharyngitis and associated high grade fevers,
should undergo a careful and thorough examination of the neck and
blood cultures as part of the initial workup. Mortality and morbidity is
low if diagnosed and treated early.